Despite the proliferation of therapies, congestive heart failure (HF) remains a progressive disease. The impact of angiotensin converting enzyme inhibitors (ACEI) and b-blockers has translated into more sustained benefit, but many patients become intolerant to b-blockers in late stage disease. There is therefore a desperate need for innovative rather than incremental therapies to reverse the course of ventricular dysfunction. HF induced by genetic or specific conditions, such as coronary artery disease, hypertension, diabetes, infection, or inflammation results in a heterogeneous myocardium consisting of a mixture of replacement fibrosis, dysfunctional and normal myocytes. The normal myocytes that remain are under continuous stress from hormonal and physical stimuli that can induce apoptosis and cell death or render them dysfunctional. Thus, their preservation is the target of current therapies with neurohormonal blockade. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed some cardiovascular diseases within reach of gene-based therapies. One of the key abnormalities in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which is responsible for abnormal intracellular Ca2+ handling. Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a), which is at least partially due to enhanced phospholamban (PLN) inhibition. Restoring SERCA2a levels or reducing PLN inhibition has been shown to improve function, metabolism and/or survival in rodent models of heart failure. More recently, we have shown that by constitutively activating the inhibitor of protein phosphatase 1 (I-1) within the failing heart, there is improvement of SR Ca2+-handling, contractility and, most importantly, reversal of adverse remodeling by directly decreasing fibrosis and cardiac hypertrophy. We therefore propose to take advantage of novel vectors, which we have developed for cardiac specific gene transfer to directly target cardiac I-1. These novel cardiotropic vectors, which are also known as Bio Nano Particles (BNP), are based on recombinant adeno-associated virus technology which exhibit very high cardiac tropisms. Combining these novel cardiotropic vectors with an important intracellular target may provide a novel paradigm for the treatment of heart failure. PUBLIC HEALTH RELEVANCE: Over the last ten years, we have undertaken a program of targeting important calcium cycling proteins which has led to the first in man clinical trial of gene therapy for heart failure using adeno-associated type 1 (AAV) vector carrying the cardiac Sarcoplasmic Reticulum Calcium ATPase pump (SERCA2a). The use of AAV serotypes for gene delivery is limited in that they are not specific for the heart. We have developed a cardiotropic chimeric of AAV that specifically targets the heart and escapes the inherent immunity in patients and it is this new cardiotropic vector when combined with a novel well validated target that will offer a new paradigm for the treatment of heart failure.